Substance abuse and dependence are characterized by substance craving, seeking, and use with loss of control in limiting intake of the substance. These behaviors occur despite significant substance use related problems and at the expense of other behaviors. In 2004, approximately 22.5 million Americans aged 12 or older needed treatment for substance (alcohol or illicit drug) abuse. The latest estimate for the costs to society of illicit drug abuse alone is $181 billion (2002).
The problem of cocaine abuse and dependence is a major medical, social, and legal concern. According to the 2005 National Survey on Drug Use and Health, approximately 13.9% of Americans aged 12 and older have tried cocaine at least once in their lifetimes and 3.3% have tried crack cocaine at least once in their lifetimes. More troublesome, in 2005, there were 2.4 million persons who were current cocaine users, which is greater than in 2004 when the number was 2.0 million. Similarly, the number of current crack users increased from 467,000 in 2004 to 682,000 in 2005. In 2004, the Drug Abuse Warning Network estimated 940,953 drug-related emergency room visits nationwide, and cocaine was the involved in the majority of these.
Clearly, there is a need for a broadly effective treatment approach, and one including a medication component may be more effective than current behavioral treatments such as cognitive behavioral therapy or contingency management alone. A variety of treatments have been studied in clinical trials, without noteworthy success. In particular, numerous randomized controlled clinical trials of antidepressants have been completed, including trials of desipramine, fluoxetine, bupropion, and imipramine. Clinical trials of mood stabilizers, including carbamazepine and lithium have also been completed, as have trials of phenyloin, direct or indirect dopamine agonists, including bromocriptine, pergolide, amantadine, mazindole, and methylphenidate. A range of other agents, including ritanserin, gepirone, nimodipine, and naltrexone have been studied as well. None of these compounds has proved reliably efficacious. Several medications acting on GABA systems have been evaluated as treatments for cocaine dependence, including tiagabine, baclofen, and vigabatrin. Results for tiagabine have been equivocal, those for baclofen have been slightly more encouraging, though not compelling. Studies of vigabatrin have been perhaps equally encouraging, though based primarily on open-label trials. The outcomes from these development efforts have generally been discouraging.
The dopamine β-hydroxylase (DBH) inhibitor disulfuram is the most effective pharmacologic treatment for cocaine dependence currently available. Unfortunately, disulfuram non-specifically inhibits several enzymes, including aldehyde dehydrogenase and plasma esterases. Disulfuram and related compounds chelate copper, which is a necessary cofactor for a variety of enzymes, including aldehyde dehydrogenase, plasma esterases and DBH. By inhibiting aldehyde dehydrogenase, disulfuram alters the metabolism of alcohol (ethanol), producing the disulfuram-ethanol reaction. This reaction consists of flushing, nausea, and hypotension.
Inhibition of plasma esterases slows the elimination of cocaine, which can result in elevations in plasma cocaine levels. In laboratory studies evaluating effects of intranasal cocaine during treatment with disulfuram, disulfuram treatment markedly increased plasma cocaine levels. Increased cocaine levels were not associated with alterations in physiologic or subjective effects of cocaine, however. Six-fold elevations in plasma cocaine levels were observed in one controlled study, and greater elevations may occur in the context of uncontrolled illicit use. A subsequent study using IV cocaine dosing documented that disulfuram slowed the elimination of cocaine, presumably by inhibiting plasma esterases. Slow absorption following intranasal dosing accounted for the increases in plasma concentrations observed earlier.
Several studies have shown preliminary efficacy of disulfuram as a treatment of cocaine dependence. In human laboratory studies, treatment with disulfuram reduced the positive subjective effects produced by cocaine. Patients with comorbid alcohol and cocaine dependence had improved outcomes when treated with disulfuram, up to 500 mg. Similarly, buprenorphine-maintained opiate- and cocaine-dependent patients reduced cocaine use during treatment with disulfuram. Recently, results from a large clinical trial suggested that disulfuram 250 mg per day was associated with reduced cocaine use compared to placebo, regardless of alcohol use pattern or type of psychotherapy provided. In this study, 112 cocaine-dependent volunteers were randomized to placebo or disulfuram, and provided one of two psychotherapies. Disulfuram treatment was associated with reduced cocaine use documented by the provision of fewer cocaine-positive urine samples compared to placebo treatment. The effect size was modest and this outcome remains to be replicated.
Disulfuram inhibits DBH, the single enzyme that mediates the synthesis of norepinephrine (NE). DBH is expressed in noradrenergic neurons and is localized within synaptic vesicles and is released along with NE. DBH can be measured in the plasma, and the concentration of DBH is highly heritable and variability in activity is largely accounted for by variability at the DBH locus. The T variant (−1021C→T) is associated with diminished DBH gene transcription and with lower DBH activity. This allele is fairly common. The frequency of the T allele is reported to be 20% among African-Americans, 22% among Northern European Americans and 16% among Japanese. The corresponding haplotype frequencies are 0.32, 0.34, and 0.09 for these populations, respectively.
Several reports indicate that disulfuram is more effective in patients with lower DBH activity. It has been shown that in subjects with low DBH activity, the proportion of cocaine-positive urines decreased over time during treatment with disulfuram 250 mg/day relative to placebo but significantly increased over time during treatment with 62.5 mg and 125 mg disulfuram/day (p's<0.04). In those with high DBH activity, the proportion of cocaine-positive urines increased over time with disulfuram at 62.5 mg/day relative to placebo (p=0.001). Thus, the efficacy of 250 mg/day disulfuram treatment appears limited to those with low DBH activity, which corresponds to the C→T genotype. Doses of disulfuram lower than 250 mg/day appear to increase cocaine use, possibly by reducing cocaine clearance by inhibiting plasma esterases, thus increasing the abuse-related euphoric effects of cocaine.
Disulfuram more effectively reduces cocaine use in patients with the DBH C→T genotype associated with lower DBH activity. Presumably, disulfuram more completely inhibits DBH in those with lower DBH activity, so that disulfuram is more effective in those with the lower activity C→T genotype. The observation that disulfuram is more effective in patients with the low-activity DBH C→T genotype confirms that inhibition of DBH is a key mechanism of action for disulfuram as a therapy for cocaine dependence.
While disulfuram provides a proof-of-concept that DBH inhibitors are promising treatments for cocaine dependence, the usefulness of disulfuram itself as a treatment for cocaine dependence is severely limited by its interactions with alcohol and cocaine.